CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells.
CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells.
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DOI：
10.1158/0008-5472.can-12-4134
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发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Jurutka PW
中科院分区：
文献类型：
--
作者：
Jacobs ET;Van Pelt C;Forster RE;Zaidi W;Hibler EA;Galligan MA;Haussler MR;Jurutka PW
维生素D是一种经过充分研究的癌症化学预防和治疗药物。它的主要循环代谢产物25-羟基维生素D在肾脏和其他组织中被细胞色素P450酶CYP27B1转化为活性激素1，25-二羟基维生素D(1，25D)。然后，1，25D被CYP24A1失活并最终分解代谢。结直肠癌细胞表达细胞色素P27B1和细胞色素P24A1，它们局部调节1，25D，潜在地影响其在癌症发生中的作用。虽然1，25D抑制了癌症的生长，但编码参与1，25D动态平衡的蛋白质的基因的多态变异的影响还知之甚少。使用RXR-VDR哺乳动物双杂交(M2H)生物检测系统，我们测量了表达5个CYP27B1单核苷酸多态(SNPs)之一或4个CYP24A1 SNPs的结肠癌细胞对维生素D代谢产物的摄取和维生素D受体(VDR)途径的激活。与野生型对照相比，5个CYP27B1 SNPs中有4个降低了酶活性，而1个(V166L)SNPs提高了酶活性。对于CYP24A1，所有测试的SNPs都降低了酶活性。实时定量聚合酶链式反应分析支持M2H实验的结果。观察到的CYP功能的SNP导向变异表明维生素D的稳态是复杂的，可能受到遗传因素的影响。对1，25D代谢的全面了解可能会为治疗维生素D相关疾病和评估致癌风险提供更个性化的方法。
Vitamin D is a well-studied agent for cancer chemoprevention and treatment. Its chief circulating metabolite, 25-hydroxyvitamin D, is converted into the active hormone 1,25-dihydroxyvitamin D (1,25D) by the cytochrome P450 enzyme CYP27B1 in kidney and other tissues. 1,25D is then deactivated by CYP24A1 and ultimately catabolized. Colorectal carcinoma cells express CYP27B1 and CYP24A1 that locally regulate 1,25D with potential implications for its impact on carcinogenesis. While 1,25D inhibits cancer growth, the effects of polymorphic variations in genes encoding proteins involved in 1,25D homeostasis are poorly understood. Using an RXR-VDR mammalian-two-hybrid (M2H) biological assay system, we measured vitamin D metabolite uptake and activation of the vitamin D receptor (VDR) pathway in colon cancer cells that expressed one of five CYP27B1 single nucleotide polymorphisms (SNPs) or four CYP24A1 SNPs. Compared to the wild-type control, four of five CYP27B1 SNPs reduced enzymatic activity while one (V166L) increased activity. For CYP24A1, all tested SNPs reduced enzyme activity. Quantitative real-time PCR analyses supported the results of M2H experiments. The observed SNP-directed variation in CYP functionality indicated that vitamin D homeostasis is complex and may be influenced by genetic factors. A comprehensive understanding of 1,25D metabolism may allow for a more personalized approach toward treating vitamin D-related disorders and evaluating risk for carcinogenesis.